Investigators of the Atlanta VA Center of Excellence for Visual and Neurocognitive Rehabilitation (CVNR) find a very high prevalence of blinding diseases in the aging veteran population. There are few treatments for the disorders that threaten our Veterans' eyesight. Our overall goal is to develop low-cost treatments that slow progressive vision loss in healthy aging or due to retinal diseases. The work proposed here is the first step in determining whether exercise can be used by aging Veterans as an inexpensive and self-controlled therapy for vision loss. Detecting the effects of an intervention on human subjects may take several years or decades. In order to translate exercise therapy for vision into the clinic, we need to identify biomarkers that can be used to predict visual benefits. Though human and animal studies show that aerobic exercise is beneficial to specific central and peripheral nervous system functions, effects on the retina and vision were unknown until we recently discovered that treadmill exercise directly protects retinal neurons in mice undergoing light-induced retinal degeneration (LIRD). In addition, we found that exercise increased levels of brain-derived neurotrophic factor (BDNF) in serum, hippocampus, and retina whereas treatment of mice with a BDNF inhibitor prevented the protective effects of exercise. Because the LIRD model mimics several aspects of human retinal diseases, including AMD, our work generated excitement in the national and international press, where it was discussed as a potential therapy for blinding diseases related to aging. Separately, in three VA-funded studies, we developed a 12-week bicycle spin exercise regimen that significantly improves cognition in healthy aged humans and in Parkinson's Disease patients. Adherence is very high (over 90%), suggesting that this is a reliable approach to altering beneficial activity for Veterans. Our studies and those of others suggest that circulating trophic factors vary with changes in exercise regimens and therefore may be used as a potential biomarker for the neuroprotective effects of exercise. For instance, increased physical activity in both mice and humans increases circulating BDNF and promotes beneficial outcomes. However, it is unknown whether circulating BDNF levels correlate with visual outcomes and could be used as a predictive biomarker in slowly progressing retinal diseases. We hypothesize that optimizing exercise regimens to increase circulating BDNF will provide the best outcomes. In Aim 1 we will test whether varying treadmill exercise regimens increase levels of serum BDNF and improve the retinal protection of mice undergoing LIRD. Outcomes will include retinal function assessed by electroretinogram (ERG) and acuity and contrast sensitivity assessed by optokinetic tracking (OKT) and BDNF levels. In vivo morphology will be assessed by optical coherence tomography (OCT). In Aim 2 we will assess visual outcomes and serum BDNF in human subjects before, during, and after aerobic exercise. Subjects currently enrolled in a 12-week CVNR study examining the effects of aerobic exercise on cognition will have visual testing (ERG, visual acuity, contrast sensitivity, and OCT) and blood collection prior to, during and after our standardized 12-week aerobic exercise regimen to determine whether circulating BDNF levels and visual outcomes are correlated and whether BDNF levels are altered as predicted in the animal studies from Aim 1. This study will determine the feasibility of biomarkers to predict sight-saving benefits of exercise. As opposed to surgery or pharmacological treatments, exercise programs provide a means for veterans to exert some control over their visual disease progression and will increase their overall health. Once the appropriate biomarkers are determined, we will submit a Merit proposal to determine the benefits of exercise in visually impaired subjects.